Silent Treatment: How Genentech, Novartis Stifled a Promising Drug

The Wall Street Journal1

APRIL 5, 2005 Silent Treatment: How Genentech, Novartis Stiﬂed A Promising Drug Biotech Firm Tried to Pursue Peanut-Allergy Injection, But Contract Got in Way Zach Avoids a ‘Kiss of Death’

By DAVID P. HAMILTON

NEWPORT NEWS, Va. – For years, the onset of the peanut harvest was enough to send Zach Williams to the hospital. Every fall, Zach’s family would watch peanut dust rise from fields to the south and trigger his allergies, making him labor for air as fluid swelled his tissues and constricted his breathing passages. Some attacks laid him in a hospital bed for weeks, where he wore an oxygen mask as drugs dripped into his veins. Five years ago Zach, then 15 years old, joined a clinical trial of an experimental drug called TNX-901, produced by Tanox Inc., a Houston biotechnology company. Monthly injections of the drug tamed Zach’s runaway immune reactions. For the first time in years, his parents sent him to school without worrying that a peanut exposure might kill him. More than 1.5 million Americans have an allergy to peanuts, and some can die in minutes if accidentally exposed. Food allergies lead to 30,000 emergency-room visits and more than 150 deaths a year, many the result of peanut exposure, says the Food Allergy and Anaphylaxis Network, a nonprofit organization in Fairfax, Va. If further testing had proven successful, TNX-901 might now be nearing approval as the first preventive treatment for these people. Instead, the drug sits on the shelf, abandoned after Tanox’s own corporate partners forced it to end development. The U.S. biotech giant Genentech Inc. and Swiss drug maker Novartis AG insisted that Tanox kill TNX-901 in favor of a Genentech drug called Xolair that has yet to prove effective against peanut allergy. When Tanox refused, its partners took it to court. The ensuing legal fight to kill TNX-901 spanned five years and consumed well over $100 million in legal fees. The battle over TNX-901 highlights a common paradox in the drug business. While companies sell many drugs that help both patients and their bottom lines, they can sometimes also advance their commercial interests by stifling potential medical advances. That may mean postponing in-house projects to prevent competition with a drug the company already sells or demanding a halt to allegedly patent-infringing research at a rival. TNX-901 represents an unusual twist on such cases: Genentech and Novartis, relying on disputed contract language, successfully blocked a third, independent company from moving ahead with a promising drug – despite the absence of alternative treatments at the time. The long court record provides a window into the vigor with which big companies can fight to stop a potential breakthrough. “It’s critical that we get that clinical trial . . . shut down,” a lawyer representing Genentech told a judge in 2000, referring to the TNX-901 trial that Zach later joined. No one knows whether TNX-901 would have ultimately proven successful. Regulatory approval would have required more rigorous testing. In the trial Zach joined, tests in more than 80 people showed that TNX-901 could bolster their tolerance to the equivalent of nine whole peanuts. Those receiving a placebo could tolerate less than half a peanut. Novartis declined to make officials available for comment. Genentech officials cast the fight with Tanox as a straightforward contract dispute, and otherwise declined to comment. Tanox itself, despite its long resistance, ultimately gave up and signed a settlement with Novartis and Genentech in February 2004. The three companies agreed to start testing Xolair as a peanut-allergy treatment. In a joint statement to The Wall Street Journal, the three say their current focus on Xolair is “the most

1 rapid and efﬁcient approach” for helping patients. Xolair, approved in 2003 as an asthma treatment, is now in mid-stage human trials for peanut allergy, and those tests may produce data sometime next year. Formal approval by the Food and Drug Administration for use in peanut allergy could take years more. Like other food sensitivities, peanut allergy is growing more common in the U.S., particularly among children. A 2003 study found that the incidence of peanut allergy in children doubled between 1997 and 2002 for reasons no one fully understands. LaDonna Williams knew her son Zach faced a lifetime of allergies almost from the moment he was born red and wheezing in 1985. Tests by Hugh Sampson, an allergy specialist then at Duke University, showed a severe allergy to peanuts. In subsequent years, Zach would keep his distance from outside food to avoid trace amounts of peanut or oil that might cling to utensils or cooking surfaces. When the family ate at a local Italian restaurant, Zach’s mother would bring her own spaghetti and meatballs, ask for a plate and wash it in the bathroom before serving Zach’s meal on it. In 2000 Dr. Sampson, who had moved to Mount Sinai Medical Center in New York, called Ms. Williams with news of a potentially life-changing drug. It was TNX-901, and the Williamses jumped at the chance to enroll Zach in a clinical trial. The odyssey of TNX-901 began with an allergy-prone molecular biologist, Tse-wen Chang, and his wife, Nancy, a fellow scientist. The Taiwanese couple founded Tanox in 1986 and soon embarked on a project to attack allergic inﬂammation. Their target: an immune-system antibody known as immunoglobulin E, or IgE. Floating through the bloodstream and across mucous membranes, the Y-shaped IgE molecule sweeps up viral and bacterial particles in its outstretched arms, and then docks its tail to a particular immune-system cell. That alerts the body’s defenses, usually triggering sneezing, rashes and watery eyes – the body’s somewhat crude initial attempt to expel invaders.

Life-Threatening Reaction Unfortunately, in some people IgE also grabs innocuous substances such as pollen or peanut protein, making the body respond to a nonexistent threat. In some allergies, such as sensitivity to peanuts or penicillin, such reactions can escalate to life-threatening anaphylactic shock. Other researchers had long tried to block IgE with experimental drugs but failed because the drugs themselves triggered allergic reactions. Tse- wen Chang thought Tanox could tailor-make a genetically engineered antibody that would latch onto IgE’s tail, preventing it from docking and setting off an allergic reaction. Tanox scientists created several such antibodies. One was TNX-901. Like many young biotech companies, Tanox was chronically short of cash. Nancy Chang, who handled the company’s business side, looked for a corporate partner and found interest from Genentech and Ciba-Geigy of Switzerland, which later merged with another Swiss company in 1996 to become Novartis. In 1989, Dr. Chang sent data and samples of an early anti-IgE antibody to Genentech, but talks with Genentech foundered. Tanox then signed a partnership with Ciba in mid-1990. Worried that the anti-IgE project might stall in Ciba’s bureaucracy, Tanox negotiated a provision allowing it to move ahead with any antibody candidate that Ciba rejected. A few years later, Genentech unveiled its own anti-IgE program, one that Dr. Chang says she considered suspiciously familiar. Tanox filed suit in Harris County district court in December 1993 accusing Genen- tech of misappropriating its work. The case dragged on into 1996, and Tanox officials began to fear that Genentech was outgunning them in the development race. Eventually, the three companies reached a deal. Genentech, Ciba (soon to be renamed Novartis) and Tanox would combine their anti-IgE programs. Genentech and Ciba would take the lead in testing, manufacturing and selling any resulting drugs. Tanox, meanwhile, licensed its anti-IgE patents to the partnership in exchange for royalties and other rights. The deal explicitly incorporated the 1990 Ciba-Tanox pact – but, significantly, it failed to clarify whether Tanox still had the right to independently develop any anti-IgE drug rejected by the bigger partners.

2 The two big companies quickly chose Genentech’s anti-IgE antibody — the future Xolair — as the partnership’s lead candidate. TNX-901 was relegated to backup status. Tanox executives began to get frustrated when the bigger partners insisted on testing Xolair solely as an asthma and hay-fever treatment, says David Anderson, a former Tanox vice president. Tanox wanted to go after food allergies, too. In mid-1997, Tanox told Genentech and Novartis that it would assert its rights to study TNX-901 in medical conditions the collaboration wasn’t addressing.

Back to Court Tanox argued that Genentech and Novartis had effectively rejected TNX-901 — triggering the old clause that said Tanox could research such drugs on its own. Not so, said the two big companies. They maintained that all anti-IgE drugs identified before the formation of the three-way collaboration belonged to the partnership, whether or not it was actively working on them. In April 1999, Genentech and Novartis sued Tanox in federal district court and demanded that it stop working on TNX-901. Tanox refused, and soon after started the clinical tests of TNX-901 that involved Dr. Sampson and Zach Williams. Zach joined the trial in October 2000. Several months later, a test revealed that his tolerance had risen substantially, apparently thanks to TNX-901. Zach’s reactions to the dust from peanut harvests ceased. When he accidentally ate some jelly beans made in a factory that also processed peanuts, he didn’t feel a thing. For Ms. Williams, a 15-year burden lifted. She was no longer plagued by the fear that an unsuspecting girl would eat a peanut-butter candy, then grab her attractive son and plant a kiss on his lips. “It would literally be the kiss of death,” she says. Genentech and Novartis were worried about the commercial threat TNX-901 might pose to Xolair, court documents show. At the time, Genentech and Novartis weren’t testing Xolair against food allergies, but their officials could foresee the possibility that they might end up competing against their own business partner. In 2001, Genentech General Counsel Stephen Juelsgaard blasted “Tanox’s unilateral decision to compete against the collaboration” and noted concerns that TNX-901 might “compete with the Xolair antibody.” In a mid-2000 courtroom status conference, an outside lawyer for Genentech, Dana Haviland, told presiding U.S. district judge Marilyn Patel that Tanox’s tests of TNX-901 threatened the “heart” of the collaboration and the coming launch of Xolair. “We really need to not have a competing product in the market from our strategic partner,” Ms. Haviland said. Judge Patel urged a settlement. One day she surveyed the attorneys in her courtroom and declared: “This is why you never had an agreement that you could agree upon. . . . There are too many lawyers.” Later, she added, “I can’t imagine this is really helping, you know, further the cause of medicine and science or anything else.” On Oct. 9, 2001, Judge Patel ruled the partnership agreements allowed Tanox to pursue TNX-901. But Genentech and Novartis quickly asked the judge to suspend the case and let them proceed with arbitration, which Tanox had earlier sought. Judge Patel agreed. A year later, an arbitrator ruled that Tanox had no right to work on TNX-901. Nancy Chang decided to end a multiyear fight that she says had cost Tanox as much as $75 million. “The biggest lesson was that money is more important than right or wrong,” she said in an interview last year. The joint statement by Genentech, Novartis and Tanox issued to the Journal says Dr. Chang’s comments reflected a “general feeling about the legal system” and didn’t specifically refer to the dispute with Genentech and Novartis. The statement says Tanox is “fully supportive” of the partnership’s decision to pursue Xolair against peanut allergy. As a bittersweet coda, Dr. Sampson and his team published findings from the TNX-901 trial in the New England Journal of Medicine in March 2003, triggering a wave of publicity and lifting the spirits of allergy

3 sufferers. But the drug was on its last legs. In February 2004, the two sides settled remaining litigation. Tanox agreed to drop TNX-901 and forgo certain rights to Xolair in exchange for a payment of $6.6 million. At the same time, Genentech and Novartis announced plans to test Xolair against peanut allergy. The drug is similar to TNX-901, so researchers like Dr. Sampson think it will also work well against food allergies. No one will know for certain, however, until results of that 150-person trial are released. Even if successful, the delay in bringing a peanut-allergy treatment to market would be significant since TNX-901 completed its similar trial in 2001. The three-company statement defends the decision to go with Xolair, noting that it has an extensive safety record because it was tested in more than 6,000 asthma patients. It states that doctors and allergists are gaining experience with the drug and that Xolair can easily be manufactured in large quantities, neither of which was true of TNX-901. Since Xolair is already approved as an asthma treatment, doctors could in theory prescribe it “off label” for peanut allergy as well. That might be risky, though, because no one knows the proper dose for peanut allergy. People receiving too low a dose might relax their watchfulness and end up in the emergency room. In addition, insurers generally don’t cover off-label drug use so most patients would have to pay thousands of dollars a year out of pocket. Tanox is now pursuing an AIDS treatment and drugs targeting asthma and inflammatory diseases. Nine- teen years after its founding, the company is still unprofitable. Tanox still supplies TNX-901 to former clinical-trial patients such as Zach Williams via the study’s original researchers. But patients typically must travel at their own expense to clinics in New York City or Denver, and some have been asked to pay several hundred dollars a month to cover the cost of administering the drug. Gregory Rogers, a 51-year-old Monument, Colo., carpenter who participated in a TNX-901 trial, stopped taking the drug last summer because he couldn’t afford it. Other allergies like hay fever and a serious skin rash, once also suppressed by the drug, have come roaring back. “After having that [drug] for a while, I sure got spoiled,” he says.

Write to David P. Hamilton at [email protected]

The Wall Street Journal2

MAY 19, 2005 Xolair Is the Better Drug for Peanut Allergy Therapy

We are writing to express our disappointment and strong exception to your page-one article “SilentTreat- ment: How Genentech, Novartis Stiﬂed a Promising Drug” (April 5). The article included an incomplete discussion of the scientiﬁc facts regarding the development of a potential therapy for peanut allergies. Be- cause science is at the center of our efforts to develop a treatment for peanut allergy, the article’s neglect of some important facts had the potential to be misleading to your readers. Genentech, Novartis and Tanox together strived to identify the most promising medicine that could be brought to patients with peanut allergies most rapidly. The fundamental question was simply, what was the best way to develop an effective treatment for patients suffering from peanut allergy quickly and safely? Two similar compounds with an identical mechanism of action — Xolair, which was on the market, and TNX-901, in early development – were considered as potential drug candidates to treat peanut allergy reactions. Because Xolair was already on the market and TNX-901 would require many years of development activities, Xolair was chosen as the most promising project.

4 It is imperative that we conduct the right trials to determine safety and efﬁcacy. Xolair already has a record of safety and efﬁcacy based on trials involving more than 6,000 patients as well as physician prescriptions for more than 40,000 patients. TNX-901 did not have a similar patient database. Secondly, Xolair already had a well-developed, FDA-approved manufacturing process and was on the market for a different indication. Therefore, the best way to move forward as quickly as possible for treating peanut allergies was to focus the trial program on Xolair. Genentech, Novartis and Tanox have always focused on bringing innovative medicines to patients as quickly as possible, and we have kept this mission at the center of our efforts in developing a treatment for peanut allergies.

Susan Desmond-Hellmann, M.D. President, Product Development Genentech South San Francisco, Calif.

James Shannon, M.D. Global Head, Clinical Development & Medical Affairs Novartis Pharma AG Basel, Switzerland

Ashraf Hanna, Ph.D., M.D. Vice President, Strategic Planning Tanox Houston The Wall Street Journal3

Thursday, February 26 2004 Tanox, Genentech and Novartis Settle Disputes Surrounding Xolair(R) And TNX-901

Tanox, Inc. (Nasdaq:TNOX), Novartis Pharma AG, an affiliate of Novartis AG (NYSE:NVS) and Genen- tech, Inc. (NYSE: DNA) announced today that they have settled all litigation among them and finalized the detailed terms of their three-party collaboration,begun in 1996, to develop and commercialize certain anti-IgE antibodies including Xolair(R) (omalizumab) and TNX-901. The following details of the settlement were disclosed: Genentech and Novartis will each reimburse Tanox $3.3 million for a portion of its TNX-901 development costs; Tanox will relinquish any rights to manufacture Xolair and, in exchange, will receive payments tied to the quantity of Xolair produced; and Tanox will benefit from an accelerated forgiveness of a loan to finance the construction of its biologics manufacturing plant in the mid-1990s. As in the original agreement, Genentech and Novartis share U.S. marketing rights for all collaboration products, while Novartis has marketing rights outside the U.S. The existing royalty and profit-sharing percentages will remain unchanged. Committees with representatives from all three companies have been established to cooperatively oversee further development and commercialization of Xolair, and possibly other collaboration products. “We are pleased to end the disputes with respect to Xolair and TNX-901 and look forward to working with Genentech and Novartis to further develop and support anti-IgE therapy for asthma and allergy,” said Nancy Chang, CEO of Tanox.

5 Peanut allergy The partners are committed to developing Xolair as the lead antibody for peanut allergy. An Investigational New Drug (IND) application for Xolair in this indication was ﬁled with the U.S. Food and Drug Adminis- tration (FDA) in November 2003. Patient enrollment in a Phase II proof of concept clinical trial is expected to begin early this year.

About Tanox Tanox, Inc. is a biopharmaceutical company with demonstrated expertise in monoclonal antibody tech- nology. The Company is engaged in the discovery and development of therapeutic monoclonal antibodies designed to address significant unmet medical needs in the areas of asthma, allergy, inflammation and other diseases affecting the human immune system. In June 2003, the FDA approved Xolair(R) (omalizumab) For Subcutaneous Use for treatment of adults and adolescents (12 years of age and above) with moderate- to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Xolair, Tanox’s first approved drug, is an anti-immunoglobulin E, or anti-IgE, antibody that was developed under a collaboration agreement among Genentech, Inc., Novartis Pharma AG and Tanox. This release and other information about Tanox, Inc. can be found on the World Wide Web at http://www.tanox.com . This release contains certain “forward-looking statements” relating to the expected timing of patient enrollment in a Phase II proof of concept clinical trial. Those statements reflect the current views of Tanox with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could affect the actual timing of trial enrollment, including but not limited to the discussions with the FDA, recruitment of investigators and study site initiation.

SOURCE Tanox, Inc.

The Wall Street Journal4

JANUARY 16, 2006 Genentech Stops Trial on Concerns Over Safety of Peanut-Allergy Test

By DAVID P. HAMILTON

Genentech Inc. stopped a clinical trial of a drug it hopes can be used to prevent peanut-allergy reactions, citing safety concerns not with the drug itself but with an allergy test. The South San Francisco, Calif., biotechnology company said two children in the 150-person trial experienced “severe hypersensitivity reactions” when given a trace amount of peanut protein, an initial step designed to gauge the severity of a patient’s allergies. Neither child had received the drug, called Xolair, the company said. Xolair is on the market, approved as a treatment for allergic asthma. “We had always been very nervous about that study,” said Susan Desmond-Hellmann, head of product development for Genentech. “We are not going to do that anymore.” Cancellation of the Xolair trial means that an approved treatment for peanut allergy remains years away at the earliest. Dr. Desmond-Hellmann said Genentech may explore the possibility of moving straight to a large-scale trial that wouldn’t involve a peanut “challenge,” as the allergic-reaction test is called. Instead, such a trial might track volunteers over an extended period of time, to determine if those receiving Xolair experienced fewer accidental peanut reactions than those taking a placebo.

6 “It’s going to take a long time, and it’s going to be hard work, but it’s better than exposing someone we know to be allergic” to peanuts, Dr. Desmond-Hellmann said. The setback is the latest delay in a long and fitful effort to find a drug that can blunt the serious con- sequences of peanut allergy. The condition, which affects an estimated 1.5 million Americans, can lead to life-threatening anaphylactic shock if allergic individuals ingest even a trace amount of peanut flour or oil. In November, a 15-year-old Canadian girl with the allergy died reportedly after a kiss from her boyfriend, who had earlier eaten a peanut-butter snack. Several years ago, a drug called TNX-901 from a Houston biotechnology company called Tanox Inc. appeared to reduce peanut sensitivity in a similar clinical trial of allergic individuals. But Tanox’s corporate partners, Genentech and Novartis AG, objected to continued development of the drug, wanting to focus on Xolair instead. After years of legal tussles, Tanox agreed to shelve TNX-901 in early 2004. The decision to shelve Tanox was the subject of a page-one article last year in The Wall Street Journal. The three companies next agreed to test Xolair as a possible peanut-allergy treatment. The clinical trial was similar to the earlier test of TNX-901, and some researchers had anticipated that it might produce results later this year. Volunteers, however, were slow to sign up, Genentech officials said.

Write to David P. Hamilton at [email protected]

The Wall Street Journal5

NOVEMBER 10, 2006 Genentech to Acquire Asthma-Drug Partner Tanox

By DAVID P. HAMILTON

Genentech Inc. agreed to acquire Tanox Inc. for $919 million, allowing the larger biotechnology concern to absorb a smaller partner that once posed a potential competitive threat. The agreement — which the South San Francisco, Calif., company said is the first acquisition in its 30-year history — highlights the hot market for acquisitions of biotech companies. With the exception of the Genentech-Tanox deal, pharmaceutical companies and large biotechs have snapped up seven smaller biotech concerns at a total cost of more than $16 billion in the past two months. “It looks like the party is going to continue for a while, when even Genentech steps up,” said Geoffrey Porges, an analyst with Sanford C. Bernstein & Co. Genentech, Tanox and Novartis AG of Switzerland worked together to develop Xolair, a drug for allergic asthma that had U.S. sales of $107 million in the third quarter. Starting in the late 1990s, however, the three companies battled over Tanox’s attempt to independently develop a similar drug called TNX-901 as a preventative treatment for potentially fatal peanut allergy. The fight over TNX-901 spanned five years, during which a midstage clinical trial suggested that the drug could mitigate the peanut-allergy effects. Tanox, of Houston, won a federal lawsuit, allowing it to continue the drug’s development, but subsequently ended up in an arbitration proceeding that ruled against the smaller company. The three companies settled the matter in 2004, with Tanox agreeing to drop TNX-901 development in exchange for $6.6 million. Although the three companies agreed to proceed with a test of Xolair against peanut allergy, Genentech canceled that trial nearly a year ago after two children experienced severe reactions to an allergy test before receiving the drug. Genentech officials have said they are interested in devising a new trial, but haven’t announced plans for further testing in peanut allergy. Tanox has several potentially promising drug candidates under development, including an AIDS drug designed to prevent HIV from entering cells. Genentech Chief Financial Officer David Ebersman, however, said the deal primarily aims to improve Genentech’s return on sales of Xolair.

7 With the acquisition, Genentech will hold onto Tanox’s share of Xolair-related royalties, proﬁt-sharing and manufacturing-related payments, which analysts estimate at between 8% and 12% of the drug’s net sales. As a result, the deal will add “modestly” to the company’s bottom line starting in 2008, Mr. Ebersman said.

Write to David P. Hamilton at [email protected]

The Wall Street Journal6

AUGUST 3, 2007 Genentech Completes A Deal to Buy Tanox

By DAVID P. HAMILTON

Genentech Inc. said it completed its $20-a-share, or $919 million, acquisition of its asthma-drug collab- orator Tanox Inc., following expiration of the waiting period under the Hart-Scott-Rodino Act. Genentech, Tanox and Novartis AG worked together to develop Xolair, a drug for asthma that had U.S. sales of $120 million in the second quarter, a 14% increase over the year-earlier period. Under the deal, Genentech, of South San Francisco, Calif., will halt its royalty payments to Tanox, and will collect them from Novartis. Xolair recently received a black-box warning from the Food and Drug Administration cautioning physi- cians and patients about the risks of anaphylaxis, a severe immune reaction. The biotech giant had collabo- rated on Xolair for over a decade with the small Texas based biotech amid periods of rivalry. While the asthma drug was the main driver of the deal, a Genentech spokeswoman said that the company is interested in several Tanox experimental drugs including other compounds against asthma, eye disease and AIDS.

Notes

1http://online.wsj.com/article/SB111265511632497703.html 2http://online.wsj.com/article/SB111645532618537399.html 3http://www.prnewswire.com/news-releases/tanox-genentech-and-novartis-settle-disputes- surrounding-xolairr-and-tnx-901-71837927.html 4http://online.wsj.com/article/SB113737301838547294.html 5http://online.wsj.com/article/SB116313101820019558.html 6http://online.wsj.com/article/SB118609942303686786.html

The new england journal of medicine

original article

Effect of Anti-IgE Therapy in Patients with Peanut Allergy

Donald Y.M. Leung, M.D., Ph.D., Hugh A. Sampson, M.D., John W. Yunginger, M.D., A. Wesley Burks, Jr., M.D., Lynda C. Schneider, M.D., Cornelis H. Wortel, M.D., Ph.D., Frances M. Davis, Ph.D., John D. Hyun, B.S., and William R. Shanahan, Jr., M.D., for the TNX-901 Peanut Allergy Study Group*

abstract

background From the National Jewish Medical and Re- Peanut-induced anaphylaxis is an IgE-mediated condition that is estimated to affect search Center, Denver (D.Y.M.L.); Mount Si- 1.5 million people and cause 50 to 100 deaths per year in the United States. TNX-901 is nai School of Medicine, New York (H.A.S.); Mayo Clinic, Rochester, Minn. (J.W.Y.); Arkan- a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an sas Children’s Hospital, Little Rock (A.W.B.); epitope in the CH3 region of IgE responsible for binding to the high-affinity Fce recep- Children’s Hospital, Boston (L.C.S.); Clin- tor on mast cells and basophils. Quest, Marlborough, Mass. (C.H.W.); and Tanox, Houston (F.M.D., J.D.H., W.R.S.). Address reprint requests to Dr. Sampson at methods the Department of Pediatrics, Box 1198, We conducted a double-blind, randomized, dose-ranging trial in 84 patients with a his- Mount Sinai School of Medicine, 1 Gustave L. Levy Pl., New York, NY 10029-6574, or at tory of immediate hypersensitivity to peanut. Hypersensitivity was confirmed and the [email protected]. threshold dose of encapsulated peanut flour established by a double-blind, placebo-controlled oral food challenge at screening. Patients were randomly assigned in a 3:1 ratio *The members of the study group are listed in the Appendix. to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge within two to N Engl J Med 2003;348:986-93. four weeks after the fourth dose. Copyright © 2003 Massachusetts Medical Society. results From a mean base-line threshold of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of TNX-901, 1650 mg in the group given 300 mg of TNX-901, and 2627 mg in the group given 450 mg of TNX-901 (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). TNX-901 was well tolerated.

conclusions A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg), an effect that should translate into protection against most unintended ingestions of peanuts.

986 n engl j med 348;11 www.nejm.org march 13, 2003

The New England Journal of Medicine Downloaded from www.nejm.org at THE UNIVERSITY OF IOWA on September 27, 2010. For personal use only. No other uses without permission. Copyright © 2003 Massachusetts Medical Society. All rights reserved.

anti-ige in peanut allergy

eanut allergy is characterized by ue. Systemic corticosteroids, beta-blockers, and ace- p symptoms and signs after ingestion that tylcholinesterase inhibitors were prohibited before may include nausea, vomiting, diarrhea, screening and throughout the study, and aspirin, an- abdominal pain, urticaria, angioedema, broncho- tihistamines, and antidepressants were prohibited spasm, hypotension, loss of consciousness, and for three days, one week, and two weeks, respective- death.1,2 Although data from animals demonstrate ly, before skin testing or oral food challenge. Race that allergic reactions are mediated by antigen-spe- was determined by the investigators. cific IgE bound to high-affinity receptors for IgE (FceRIs) on mast cells and basophils,3,4 non-IgE study design pathways for anaphylaxis exist, at least in mice,5,6 This was a randomized, double-blind, placebo-con- and direct clinical evidence of IgE involvement in trolled, dose-ranging study. Prospective patients peanut allergy in humans is lacking. underwent a screening physical examination and Approximately 1.5 million people in the United laboratory tests. Before enrollment, allergy to pea- States have peanut allergy,7,8 50 to 100 of whom die nut was confirmed and the threshold for reactivity each year from unintended ingestion.9,10 Severe re- was established by a randomized, double-blind oral actions can occur at any age,2,11 the previous reac- food challenge, as described below. Central random- tion cannot be used reliably to predict the course ization was performed in blocks of four per site. Pa- of the next, and even the first reaction may be se- tients were randomly assigned in groups of 28 and vere.1,11-13 Current treatment for peanut allergy is in a 3:1 ratio to receive 150 mg, 300 mg, or 450 mg avoidance or rescue with epinephrine.12,14-16 Only of TNX-901 or placebo subcutaneously every four a small minority of patients who are allergic to pea- weeks for four doses. They then underwent a final nuts carry epinephrine, and even timely injection oral food challenge with peanut flour within two to may not prevent death.8,11 Avoidance is extremely four weeks after the last dose. Enrollment at each difficult,1,11,17 and the risk–benefit ratio for hyposen- dose level was completed before enrollment at the sitization is unfavorable.18 next level began. Every four weeks, blood and urine TNX-901 is a humanized IgG1 monoclonal an- samples were obtained and patients were evaluat- tibody against IgE that binds with high affinity to ed for adverse events. The final evaluation occurred an epitope in the CH3 domain, masking a region re- eight weeks after the last dose (week 20). sponsible for binding to both FceRIs and low-affin- The study was approved by institutional review ity Fce receptors (FceRII, or CD23).19-21 In addition boards at all participating centers, and all patients to inhibiting binding of IgE to mast cells and baso- provided written informed consent. The data from phils, anti-IgE also markedly down-regulates the ex- all participating centers were sent to and moni- pression of FceRIs on basophils22,23 and may inhibit tored by ClinQuest, and all data were entered and allergen-specific activation of T cells through inter- locked before data analysis commenced. The data ference with the processing of antigen-presenting were analyzed by Abt Associates Clinical Trials. The cells mediated by FceRIIs or FceRIs.24 study was designed by five of the investigators, three of whom had full access to the data. The sponsor methods did not limit the investigators’ right to publish the results. patients Patients 12 to 60 years of age with a history of pea- study drug nut allergy manifested by urticaria, angioedema, Each dose of TNX-901 and placebo was supplied as lower respiratory tract symptoms, or hypotension a 150-mg lyophilized cake in a 5-ml clear-glass vi- were eligible for enrollment. Inclusion criteria were al. A pharmacist reconstituted each cake with 1 ml a serum total IgE level between 30 and 1000 IU per of sterile water in an unblinded fashion and placed milliliter, good health, body weight within 20 per- the solution in a syringe, which was masked to pre- cent of ideal, a positive skin-prick test to peanut and vent study personnel from identifying the contents, a negative skin-prick test to tuna oil, and no prior ex- for subcutaneous injection. posure to monoclonal antibodies. Eligible patients could not be pregnant. Any asthma was to be under assessment of efficacy control, with a forced expiratory volume in one sec- The primary measure of efficacy was the change ond that was at least 80 percent of the predicted val- from base line in the threshold dose that induced

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The new england journal of medicine

hypersensitivity to peanut flour, as assessed by an in blood samples with use of a modification of the oral food challenge. The threshold dose was log- enzyme-linked immunosorbent assays described transformed (on a base 10 scale). Peanut flour was for CGP 51901, the chimeric version of TNX-901.25 made by grinding equal portions of Valencia, run- Total peanut-specific IgE was measured by a fluo- ner, and Spanish peanuts (Greer Laboratories), the rescence enzyme immunoassay (CAP-System, FEIA, types used in virtually all peanut products consumed Pharmacia Upjohn).26 in the United States. The peanuts were defatted, and then various doses (1 mg to 2 g) were loaded into gel statistical analysis capsules. Matching placebo capsules were filled The predefined primary efficacy measure was the with similar amounts of cornstarch. For masking change from base line in the log-transformed thresh- purposes, the capsules were rolled in tuna oil before old dose of peanut flour that induced hypersensi- administration. tivity. Since there were no clinical data on which to The screening double-blind, placebo-controlled estimate the variability in this measure, the sample oral food challenge was administered on two days size was estimated on the basis of a dichotomous within a five-day period. At base line, spirometry variable. Success was defined as an increase in the was performed, intravenous access established, and threshold dose of at least 0.9 log (by a factor of at continuous cardiac monitoring initiated. Vital signs least 7.9 or by three steps in the oral food challenge). were checked, chest auscultation was performed, Success constituted a secondary efficacy measure and peak expiratory flow rates were monitored ev- thought to be both clinically meaningful and un- ery 30 minutes during the food challenge and for likely to be due to placebo. Assuming a success rate at least 2 hours after the last dose or the abatement of 80 percent for TNX-901 and 20 percent for place- of any symptoms or signs. Patients were given in- bo, a two-sided type 1 error rate of 0.05, a statisti- creasing doses of placebo or peanut flour every 40 cal power of 90 percent, and a multiple-comparison minutes until the principal investigator at each site approach, 20 patients per group were required. To judged that a definite reaction was occurring. To allow for a 5 percent dropout rate, the number was maximize safety and prevent severe reactions, the increased to 21 per group. end point for the oral food challenge was the thresh- Safety and efficacy were analyzed on a predefined, old dose for an allergic reaction. At screening, the modified intention-to-treat basis. Inclusion in the initial dose was 1 mg, followed successively by 5, intention-to-treat analysis of efficacy required the 10, 20, 50, 100, 200, 500, 1000, and 2000 mg of pea- receipt of at least one dose of study drug and val- nut flour or matching placebo capsules. Patients ues for base-line and repeated oral food challenges; who could tolerate 2000 mg were considered to have safety analyses included any patient who received had a negative test. To enter the study, each patient at least one dose of study drug. For the primary ef- was required to have one positive and one negative ficacy measure, pairwise comparisons of each TNX- result at screening, under the assumption that the 901 group with placebo used Dunnett’s test based positive result was to peanut. The final oral food on an analysis-of-covariance model with terms for challenge with peanut flour alone was initiated at treatment, site, base-line weight, base-line IgE lev- 1 mg or 100 mg, depending on the screening thresh- els, and base-line peanut-specific IgE levels. The pro- old, and escalated to 4000 mg and then 8000 mg if portion of patients who had an increase in the thresh- tolerated. The dose escalation was terminated when old dose of at least 0.9 log (success) was assessed an investigator believed there were clear-cut symp- by pairwise comparisons of each TNX-901 group toms or signs of a hypersensitivity reaction, and the with placebo with the use of Fisher’s exact test, with patient was then given activated charcoal slurry adjustment for multiple comparisons. All reported (Liqui-Char, Jones Pharma), which is believed to P values are two-sided. No interim analysis was con- adsorb residual peanut protein in the stomach. Spe- ducted. cific treatment protocols were followed in the event of asthma or other systemic reactions. results

assessment of serum ige, peanut-specific ige, study population tnx-901, and anti–tnx-901 antibody levels The study was conducted between July 1999 and Total IgE and free IgE (unbound by TNX-901), TNX- March 2002 at seven centers in the United States: 901, and anti–TNX-901 antibodies were measured 164 patients were screened, 84 patients under-

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went randomization, and 81 completed the study. efficacy and pharmacodynamics Two patients (one each in the 150-mg and 300-mg Allergic reactions to peanut were generally well groups) were found to have had a positive placebo controlled by termination of the oral food challenge and a negative peanut challenge at screening. For followed by the oral administration of charcoal and both, a base-line threshold dose of 2000 mg (the treatment with epinephrine, bronchodilators, anti- highest dose administered at screening) was as- histamines, and corticosteroids, as appropriate. One signed, and the threshold dose was determined to patient required overnight hospitalization for hypo- be 100 mg at the final oral food challenge. In the tension. The mean time from the final dose to the fi- 300-mg group, one patient discontinued the study nal oral food challenge was similar among the four on day 7 because of a myocardial infarction, and one groups (range, 21.2 to 24.5 days). stopped on day 43 because of a brain tumor. The ef- In all patients, the threshold of sensitivity to ficacy analyses therefore included 82 patients. A to- peanut was determined by a constellation of signs tal of 23 patients were randomly assigned to receive and symptoms typical of allergic reactions to food, placebo, 19 to receive 150 mg of TNX-901, 19 to re- at least one of which was judged to be moderate or ceive 300 mg of TNX-901, and 21 to receive 450 mg severe in nature in all but 14 of the 166 challenges of TNX-901. One patient in the 450-mg group com- to peanut flour. Nausea, abdominal pain, vomiting, pleted efficacy evaluations but withdrew consent throat tightness, chest tightness, wheezing, persist- before the final two visits. Base-line characteristics ent cough, rhinitis, conjunctivitis, pruritus, hives, were similar among the groups (Table 1). and angioedema were among the most common

Table 1. Characteristics of the Patients Included in the Efficacy Analysis.

150 mg of 300 mg of 450 mg of Placebo TNX-901 TNX-901 TNX-901 Total Characteristic (N=23) (N=19) (N=19) (N=21) (N=82)

Age (yr) Mean 34.4 34.9 28.3 31.6 32.4 Range 14–59 13–49 13–52 13–53 13–59 No. 12–17 yr of age 5 3 6 4 18 Sex (M/F) 10/13 11/8 12/7 12/9 45/37 Weight (kg) Mean 75.1 71.5 76.7 70.1 73.4 Range 59–99 45–114 43–100 45–95 43–114 Race or ethnic group (no.) White 20 16 19 20 75 Black 2 1 0 0 3 Hispanic 0 0 0 1 1 Asian 1 1 0 0 2 Other 0 1 0 0 1 Threshold sensitivity to peanut flour (mg) Mean 300.0 435.5 433.2 177.6 330.9 Range 1–2000 5–2000 5–2000 5–2000 1–2000 Serum IgE (IU/ml) Mean 251.3 349.8 205.1 286.7 272.5 Range 36–955 101–902 11–496 33–1017 11–1017 Serum peanut-specific IgE (U/ml) Mean 24.0 21.7 24.3 32.9 25.9 Range 0.34–100 0.34–100 0.34–100 0.69–100 0.34–100 Peanut-specific IgE (%) Mean 9.7 7.4 12.2 12.6 10.6 Range 0.15–42.7 0.14–30.5 0.20–34.5 0.47–30.4 0.14–42.7

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line in a dose-responsive manner. Although the in- 4400 Screening Week 14–15 crease, as compared with that in the placebo group, 3900 only reached statistical significance for the 450-mg

3400 group (P<0.001) (Fig. 1), a strong trend was associated with increasing doses (P<0.001). The propor- 2900 tion of patients who had an increase in the thresh- 2400 old of sensitivity of at least 0.9 log was greater in all 1900 the TNX-901 groups than in the placebo group, but 1400 again this difference was significant only in the 900 450-mg group (P=0.002): 22 percent in the place-

Threshold of Peanut Flour (mg) 400 bo group, 53 percent in the 150-mg group, 47 percent in the 300-mg group, and 76 percent in the ¡100 Placebo 150 mg of 300 mg of 450 mg of 450-mg group (P for trend=0.001). The propor- TNX-901 TNX-901 TNX-901 tions of patients in each group who tolerated a 0.5-, 1-, 2-, 4-, and 8-g challenge at screening and dur- Figure 1. Mean Threshold Dose of Peanut Flour Eliciting ing the final oral food challenge, at week 14 to 15, Symptoms in Patients Receiving TNX-901 or Placebo. are shown in Figure 2. In the placebo group, 4 per- The mean increase in the threshold of sensitivity, as compared with that in the placebo group, reached signif- cent of patients reached the highest level tested — icance only in the 450-mg group (P<0.001); however, re- 8 g — as compared with 0 percent of those in the sults of the test for trend with increasing doses were 150-mg group, 21 percent of those in the 300-mg significant (P<0.001). I bars are 95 percent confidence group, and 24 percent of those in the 450-mg group. intervals. Although pairwise comparisons with placebo of the proportions of patients who tolerated a given dose were not significant, significant trends with increas- signs and symptoms that led to the termination of ing dose were noted for the 4-g and 8-g threshold the oral food challenge. (P=0.02 for both). The mean threshold of sensitivity to peanut at Changes from base line in the log-transformed the final oral food challenge increased from base threshold dose correlated similarly with the dose

90 Placebo 150 mg of TNX-901 300 mg of TNX-901 450 mg of TNX-901 80

Patients (%) 30

0 g g ng ng i –15 i –15 n 4 4 4–15 4–15 ree 1 reenin 1 Screening Wk 14–15 Sc Wk 1 Screen Wk 1 Screenin Wk Sc Wk 0.5 g 1.0 g 2.0 g 4.0 g 8.0 g Threshold Dose of Peanut Flour

Figure 2. Percentage of Patients Who Tolerated Specified Dosing Thresholds during the Oral Food Challenge at Screen- ing and Week 14 to 15. Although pairwise comparisons with placebo did not reach statistical significance at any threshold level, the trend for increasing doses of TNX-901 at the 4-g and 8-g threshold levels was significant (P=0.02 for both).

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on an absolute basis in terms of milligrams of anti- IgE (Fig. 3), milligrams of anti-IgE per kilogram of 4 r=0.35 P=0.001 body weight, and milligrams of anti-IgE per kilo- 3 gram per total IgE level at base line, and these rela- tions were statistically significant. Efficacy correlat- 2 ed less well with the dose on the basis of milligrams 1

per kilogram per peanut-specific IgE level at base 0 line and milligrams per kilogram per percent of total IgE that was peanut-specific at base line, and ¡1

these correlations were not significant. Change in Threshold Dose (log) ¡2 Trough drug levels were roughly dose propor- 0 150 300 450 tional and reached steady state at week 12 (mean, Dose of TNX-901 (mg) 11.6 µg per milliliter in the 150-mg group; 32.2 µg per milliliter in the 300-mg group; and 57.5 µg per Figure 3. Scatter Plot of the Correlation between the Dose of TNX-901 and the Increase in the Threshold of Sensitivity to Peanut Flour from Screen- milliliter in the 450-mg group). Taking the trough ing to Week 14 to 15. level at week 12 as a measure of drug exposure, we Not all of the data points can be individually distinguished, since the protocol- found that the correlation between the change in the specified dose-escalation scheme for the oral food challenge limited the num- threshold dose and trough drug levels (r=0.392, ber of possible values on either an absolute or, as shown here, a log-transformed P<0.001) was similar to that between threshold dose basis; hence, many of the data points overlie one another. and the dose of TNX-901 (r=0.381, P<0.001). Serum free IgE levels were measured every four weeks, just before each injection, and substantial and consisted primarily of erythema and, to a lesser reductions were obtained and sustained at all three extent, swelling and burning. All injection-site reac- doses of TNX-901. From base-line levels of 199.5 tions were considered mild in nature except in one IU per milliliter in the placebo group, 262.0 IU per patient in the 450-mg group who had moderate milliliter in the 150-mg group, 158.9 IU per millili- erythema or edema on two occasions. There were no ter in the 300-mg group, and 242.0 IU per milliliter significant changes in the results of routine hema- in the 450-mg group, free IgE levels were 207.4 (an tologic variables (including platelet count), serum increase of 4.0 percent), 30.4 (a decrease of 88.4 chemical analyses, and urinalysis. There was no ev- percent), 17.0 (a decrease of 89.3 percent), and 16.6 idence of anti–TNX-901 antibodies in any patient. (a decrease of 93.2 percent) IU per milliliter, respectively, at the end of week 4, just before the second discussion injection, and similar reductions were observed throughout the dosing period. Eight weeks after the In the absence of reliable epidemiologic data and last dose of TNX-901, the last time point assessed, given the impracticability of conducting a large, pla- free IgE levels were still reduced from base line by cebo-controlled trial in which episodes of anaphy- 71.6 percent in the 150-mg group, 79.1 percent in laxis owing to accidental ingestions served as end the 300-mg group, and 88.7 percent in the 450-mg points, we elected to use an increase in the amount group. of peanut flour required to elicit symptoms in an oral challenge as a valid substitute. A substantial increase safety in the threshold of peanut flour required to provoke TNX-901 was well tolerated. The incidences and symptoms should serve as a proxy for the level of spectrum of systemic adverse events and local ad- protection against unintended ingestion. The dou- verse events were similar in the TNX-901 and place- ble-blind, placebo-controlled oral food challenge bo groups. The total number of systemic adverse is the standard for diagnosing food allergy and has events reported (range, 45 to 50 per group) and the been used as an efficacy end point in several stud- number of patients who had such events (range, 15 ies.17,27-30 Although we discontinued the oral food to 19 per group) were similar among the four groups. challenge only when patients had symptoms or Systemic adverse events that occurred more than signs that typically precede more severe symptoms, once in a TNX-901 group are given in Table 2. With this end point is not devoid of subjective interpre- respect to local adverse events, injection-site reac- tation, since some of these symptoms can be pro- tions were noted in 13 to 14 patients in each group duced by anxiety. Reliable confirmation of an aller-

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Table 2. Adverse Events Other Than Local Events That Occurred in More Than One Patient in a TNX-901 Group.

150 mg of TNX-901 300 mg of TNX-901 450 mg of TNX-901 Adverse Event Placebo (N=23) (N=19) (N=21) (N=21)

No. of No. of No. of No. of No. of No. of No. of No. of Patients Events Patients Events Patients Events Patients Events Diarrhea 1 1 4 5 1 1 1 2 Nausea 1 1 3 3 1 2 1 1 Vomiting 2 2 1 2 2 2 1 1 Fatigue 0 0 3 3 2 2 0 0 Fever 1 1 1 1 3 3 1 1 Food allergy* 6 7 4 4 7 7 5 6 Upper respiratory tract 7 8 7 12 10 12 3 4 infection Headache 3 4 4 5 2 2 2 2 Arthralgia 1 1 2 2 3 3 2 3

* Events related to food allergy were reported by the patient and were unrelated to oral food challenge. Reactions were due to exposure to a variety of foods, including tree nuts and seafood. Four food reactions occurred more than six weeks after the last dose of study drug: one each in the placebo, 300-mg, and 450-mg groups and two in the 150-mg group. Many of the food reactions were subjective in nature, and all were considered mild or moderate, except one event rated as severe in the placebo group. All reactions were treated expectantly or symptomatically. Approximately half the food reactions were considered mild and approximately half moderate in all groups except the 450-mg group, in which five food reactions were rated mild and only one was rated moderate.

gic response is not readily available, since plasma equivalent to approximately six and eight peanuts, histamine (a marker of the allergic response) is very respectively, and should therefore provide substan- labile and difficult to measure,31 serum tryptase tial protection in most patients. In addition, 21 per- rarely increases during allergic reactions to pea- cent of patients in the 300-mg group and 24 percent nuts,11 and signs such as the heart rate are subject of those in the 450-mg group were effectively toler- to anxiety on the part of the patient. A placebo effect ized and able to ingest at least 8 g of peanut flour was clearly seen. Two patients had negative peanut (approximately 24 peanuts), the final dose in the and positive placebo challenges at base line, with food challenge, before having a reaction. positive challenges to peanut at the final oral food In patients with peanut allergy, there is currently challenge. In spite of these limitations, in experi- no adequate treatment of or protection against the enced hands, the oral food challenge appears to be accidental ingestion of peanuts other than avoid- a reliable method of determining sensitivity to pea- ance, although epinephrine modulates the reaction nut in most patients. In general, the thresholds of and can be lifesaving. Our clinical data confirm the sensitivity to peanut flour at screening and at the fi- direct role of IgE in peanut-induced hypersensi- nal evaluation were remarkably similar in the pla- tivity reactions and demonstrate that TNX-901, at cebo group; only 5 of 23 patients had more than a a dose of 450 mg subcutaneously every four weeks, two-step increase in the threshold. significantly increases the threshold of sensitivity to Although the average amount of peanut con- peanut antigen, as assessed by oral food challenge, sumed in an accidental exposure has not been ac- to a level that should translate into at least partial curately quantified, it is generally believed to be no protection against most unintended ingestions of more than one or two peanuts, or the equivalent of peanut. Although these results are highly encourag- approximately 325 to 650 mg of peanut flour. The ing, TNX-901 is still an experimental drug, and ap- thresholds achieved in the 300-mg and 450-mg proval for general use will require confirmation of groups — 2083 and 2805 mg, respectively — are these results in additional studies.

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Supported by Tanox and in part by grants from the Peanut Board consulting fees from Unilever, Wyeth, and Monsanto; receiving a and the Peanut Foundation to Tanox and by grants from the National grant and holding stock options and related patents with SEER (for- Institutes of Health National Center of Research Resources to the merly Panacea); and receiving grants from the Peanut Board, the Na- Mount Sinai School of Medicine (MO1 RR-00071) and to the Mayo tional Peanut Foundation, Monsanto, and the Food Allergy Initiative. Foundation (MO1 RR-585). Dr. Davis, who was an employee of Tanox while the study was being Drs. Leung, Sampson, Yunginger, and Schneider have reported carried out, is currently a consultant to Tanox and has stock options receiving grant support from Tanox. Dr. Yunginger has also reported in Genentech. Mr. Hyun and Dr. Shanahan are employees of Tanox. receiving grant support from Kimberly-Clark and lecture fees from We are indebted to Sara Yankelev, M.S., and Roger Johnson, Ph.D., Aventis Pharmaceuticals. Dr. Schneider has reported receiving grants of Abt Associates Clinical Trials, Cambridge, Mass., for the statisti- from Baxter, Dyax, and Genentech. Dr. Burks has reported receiving cal analyses.

appendix The TNX-901 Peanut Allergy Study Group consisted of the following investigators: A.W. Burks, Jr., L. Christie, and K. Althage, Arkansas Children’s Hospital, Little Rock; H.A. Sampson, S.H. Sicherer, A. Nowak-Wegrzyn, and S.A. Noone, Mount Sinai School of Medicine, New York; L.C. Schneider, A. Alangari, and I. Borras, Children’s Hospital, Boston; J. Spergel, Children’s Hospital of Philadelphia, Philadelphia; S.A. Tilles, Asthma, Inc., Seattle; D.Y.M. Leung, H.S. Nelson, F.D. Atkins, and J. Murray, National Jewish Medical and Research Center, Den- ver; and J.W. Yunginger, G. Volcheck, M. DeBolt, K.A. Bachman, and C. Wiginton, Mayo Clinic, Rochester, Minn.

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